1-[17β-(acetyloxy)-3α-hydroxy-2β-(4-morpholinyl)-5α-androstan-16β-yl]-1-(2-propenyl)pyrrolidinium bromide (rocuronium bromide, Compound I) has the following structure
and a formula of C32H53BrN2O4 and a molecular weight of 609.70. Rocuronium bromide is used as a nondepolarizing neuromuscular blocking agent with a rapid to intermediate onset depending on dose and intermediate duration. It acts by competing for cholinergic receptors at the motor end-plate. This action is antagonized by acetylcholinesterase inhibitors, such as neostigmine and edrophonium.
Rocuronium Bromide is marketed in North America under the name ZEMURON®, and elsewhere under the brand name ESMERON®. It is supplied as a sterile, nonpyrogenic, isotonic solution that is clear, colorless to yellow/orange, for intravenous injection only.
The preparation of rocuronium bromide is disclosed in U.S. Pat. Nos. 5,817,803 and 4,894,369, and in U.S. publication No. 2005/0159398.
U.S. Pat. No. 4,894,369 (“'369 patent”) discloses the preparation of rocuronium bromide which is purified by chromatography followed by crystallization from dichloromethane and ether.
U.S. publication No. 2005/0159398 discloses rocuronium bromide made via a bis-acetylated intermediate, wherein Rocuronium is obtained in yields of about 87% and in a purity of 98% area by HPLC.
Like any synthetic compound, rocuronium bromide salt can contain extraneous compounds or impurities that can come from many sources such as degradation. The extraneous compounds or impurities can be unreacted starting materials, synthetic by-products, products of side reactions, and/or degradation products. Impurities in rocuronium bromide salt or any active pharmaceutical ingredient (API) are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API.
In addition to stability, which is a factor in the shelf life of the API, the purity of the API produced in the commercial manufacturing process is clearly a necessary condition for commercialization. Impurities introduced during commercial manufacturing processes must be limited to very small amounts, and are preferably substantially absent. For example, the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, dated Nov. 10, 2000) requires that process impurities be maintained below set limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time, and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.
The product mixture of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and by-products of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the product mixture. At certain stages during processing of the API, Rocuronium bromide, it must be analyzed for purity, typically, by HPLC, TLC or GC analysis, to determine if it is suitable for continued processing and, ultimately, for use in a pharmaceutical product. The API need not be absolutely pure, as absolute purity is a theoretical ideal that is typically unattainable. Rather, purity standards are set with the intention of ensuring that an API is as free of impurities as possible, and, thus, are as safe as possible for clinical use. As discussed above, in the United States, the Food and Drug Administration guidelines recommend that the amounts of some impurities be limited to less than 0.1 percent.
Generally, side products, by-products, and adjunct reagents (collectively “impurities”) are identified spectroscopically and/or with another physical method, and then associated with a peak position, such as that in a chromatogram, or a spot on a TLC plate. (Strobel p. 953, Strobel, H. A.; Heineman, W. R., Chemical Instrumentation: A Systematic Approach, (3rd ed., Wiley & Sons, New York 1989)). Thereafter, the impurity can be identified, e.g., by its relative position in the chromatogram, where the position in a chromatogram is conventionally measured in minutes between injection of the sample on the column and elution of the particular component through the detector. The relative position in the chromatogram is known as the “retention time.”
The retention time can vary about a mean value based upon the condition of the instrumentation, as well as many other factors. To mitigate the effects such variations have upon accurate identification of an impurity, practitioners use the “relative retention time” (“RRT”) to identify impurities. (Strobel p. 922). The RRT of an impurity is its retention time divided by the retention time of a reference marker. It may be advantageous to select a compound other than the API that is added to, or present in, the mixture in an amount sufficiently large to be detectable and sufficiently low as not to saturate the column, and to use that compound as the reference marker for determination of the RRT.
As is known by those skilled in the art, the management of process impurities is greatly enhanced by understanding their chemical structures and synthetic pathways, and by identifying the parameters that influence the amount of impurities in the final product.
According to the European pharmacopoeia rocuronium bromide should contain not more than 0.2% area by HPLC of impurity A. In addition according to the ICH guide lines (Q3C Impurities: Tables and list, November 2003) rocuronium bromide should contain no more than about 5000 ppm of ethyl ether, and 600 ppm of dichloromethane. The invention encompasses rocuronium bromide that exceeds the limitations set forth by the European Pharmacopoeia 5th edition (Supplement 5.4, pp. 4013-4014) and ICH guidelines.
Like any synthetic compound, rocuronium bromide can contain extraneous compounds and/or impurities that can come from many sources. They can be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products. The invention addresses these issues by providing rocuronium bromide in high purity.